The formation of lipid peroxides in the body and their associated radical reactions have recently been demonstrated to have various detrimental effects on the body resulting from membrane damage, cytotoxicity and so forth. Accompanying this finding, various attempts have been made to apply antioxidants and lipid peroxide formation inhibitors to pharmaceuticals, and research has been conducted on numerous types of antioxidants (see, for example, Non-Patent Literature 1). Known examples of these antioxidants include pharmaceutical compositions used for the treatment and prevention of endotoxin shock triggered by inflammation or infection that contain a specific quinone derivative (see, for example, Patent Literature 1), hydroxamic acid derivatives used for the treatment and prevention of autoimmune diseases having cell growth inhibitory action and vascularization inhibitory action (see, for example, Patent Literature 2), and 2,3-dihydrobenzofuran derivatives that are useful as antioxidants and radical scavengers (see, for example, Patent Literatures 3, 4 and 5). In addition, other known examples include imidazole-based compounds having anti-hyperlipemia action that are useful for the treatment and prevention of arteriosclerosis (see, for example, Patent Literature 6), and benzothiazine carboxamides represented by the following formula having anti-arthritis activity (see, for example, Patent Literature 7).

Moreover, other known examples include carbonyl aminophenyl imidazole derivatives (see, for example, Patent Literature 8, Patent Literature 9, and Patent Literature 10), aminodihydrobenzofuran derivatives having lipid peroxide formation inhibitory action that are useful as preventive and treatment agents of various diseases such as arteriosclerosis, liver disease and cerebrovascular disorders (see, for example, Patent Literature 11), anti-hyperlipemia drugs containing phenylazole compounds (see, for example, Patent Literature 12), dihydrobenzofuran derivatives that significantly improve damage caused by lipids, proteins, carbohydrates and DNA occurring as a result of oxidative stress that occurs when antioxidation defense systems are inadequate (see, for example, Patent Literature 13), and optically active aminodihydrobenzofuran derivatives that are effective for improving, treating and preventing impairment of brain function accompanying cerebral stroke or head injury.
Since the brain is dependent on circulating blood for its supply of energy despite it having a large energy demand, it is extremely susceptible to ischemia. When the brain falls into a state of cerebral ischemia as a result of having its blood flow cut off for various reasons, active oxygen species are formed triggered by mitochondrial damage and elevated calcium levels within nerve cells. In addition, oxygen radicals are known to be formed in extremely large amounts when blood flow is resumed following ischemia. These active oxygen species ultimately act on lipids, proteins, nucleic acids, or the like, which is said to result in their oxidation and cell death. Antioxidants are used to treat such a condition, and in Japan, Edaravone has been approved as a brain protective drug and is used for that purpose.
Lipoxygenase (abbreviated as LO), which adds oxygen to unsaturated fatty acids such as arachidonic acid, is known to exist in the form of 5-LO, 8-LO, 12-LO and 15-LO according to the site where oxygen is added. Among these, 5-LO is the initial enzyme in the synthesis of leucotrienes, which are potent inflammation mediators. Leucotrienes are involved in various inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory colitis and psoriasis, and their control is useful for the treatment of these diseases. 12-LO and 15-LO react with linoleic acid, cholesterol esters, phospholipids and low-density lipoproteins (hereinafter, abbreviated as LDL) in addition to arachidonic acid, and are known to add oxygen to their unsaturated fatty acids (see Non-Patent Literature 2). Macrophages become foamy cells by unrestricted uptake of oxidative-modified LDL by means of scavenger receptors, and this is widely known to be the initial step in the formation of arteriosclerotic foci. 12-LO and 15-LO are expressed in high levels in macrophages, and have been clearly demonstrated to be essential as the trigger for oxidative modification of LDL (see Non-Patent Literature 3). Their control is useful for the treatment of various types of diseases caused by arteriosclerosis (see Patent Literature 15).
Oxidative stress involving free radicals and active oxygen is thought to be one of the causative factors of many eye diseases such as cataract and macular degeneration that frequently occurs with aging (see, for example, Non-Patent Literatures 4, and 6). Among tissues of the eye, the retina along with the lens are known to be tissues that are susceptible to the effects of aging (see, for example, Non-Patent Literature 7). The retina is susceptible to the effects of various free radicals because it contains a large amount of higher unsaturated fatty acids and because it is provided with nutrients from both retinal blood vessels and choroid blood vessels and consumes a large amount of oxygen. For example, light such as sunlight that enters the eyes during the entire course of a person's life is a typical example of oxidative stress that affects the retina. The majority of the sunlight that reaches the earth consists of visible light and infrared right, while ultraviolet light that only accounts for several percent of that light has a significant effect on health by powerfully interacting with the body as compared with visible light and infrared light. Ultraviolet light is divided into UV-A (320 to 400 nm), UV-B (280 to 320 nm) and V-C (190 to 280 nm) according to differences in its wavelength, and although its action and strength relative to the body differ, ultraviolet light of 290 nm or less which exhibits particularly strong cytotoxicity has conventionally been thought to hardly reach the earth's surface at all as a result of being absorbed by the ozone layer of the stratosphere. In recent years however, the amount of ultraviolet light that reaches the earth has increased due to the appearance of ozone holes thought to be caused by destruction of the environment, and judging from rapid increases in the occurrences of skin disorders and skin cancer related to ultraviolet light in the southern hemisphere, retinopathy is expected to considerably increase due to the effects of UV-A reaching the earth's surface.
Among various eye diseases, age-related macular degeneration is a type of retinopathy associated with a high degree of vision loss. In the US, roughly 10 million people have mild symptoms of this disease, and more than 450,000 have impaired vision brought on by this disorder (see, for example, Non-Patent Literature 8). There is concern over an increased incidence of this disease in Japan as well where the number of elderly in the general population is increasing rapidly. Although there are many aspects of the mechanism of occurrence of macular degeneration that are not fully understood, the progression of this lesion has been pointed out to involve a peroxidation reaction caused by light absorption in the retina (see, for example, Non-Patent Literatures 9 and 10). In addition, the appearance of a lipofuscini-like fluorescent substance known as Druse has been observed in the early stages of its onset. Since lipofuscin is formed from the bonding of protein and aldehyde, which is a secondary decomposition product of lipid peroxides, there is the possibility that a lipid peroxidation reaction in the retina caused by ultraviolet light or visible light may induce this type of retinopathy.
Retina disease treatment agents containing a specific dihydrofuran derivative (see, for example, Patent Literature 16), and drugs for visual acuity and retinal changes, including macular changes of the retina, that contain propionyl L-carnitine or its pharmaceutically acceptable salts, and carotenoids (see, for example, Patent Literature 17), are known to be useful for the prevention and treatment of these retina diseases due to their antioxidative action.
Patent Literature 1: Japanese Unexamined Patent Application, First Publication No. S61-44840
Patent Literature 2: Japanese Unexamined Patent Application, First Publication No. H1-104033
Patent Literature 3: Japanese Unexamined Patent Application, First Publication No. H2-121975
Patent Literature 4: European Patent Application, Publication No. EP 345593
Patent Literature 5: European Patent Application, Publication No. EP 483772
Patent Literature 6: International Publication No. WO 95/29163
Patent Literature 7: German Patent Application, Publication No. DE 3,407,505
Patent Literature 8: Japanese Unexamined Patent Application, First Publication No. S55-69567
Patent Literature 9: European Patent Application No. EP 324277
Patent Literature 10: European Patent Application, Publication No. EP 458037
Patent Literature 11: Japanese Unexamined Patent Application, First Publication No. H5-140142
Patent Literature 12: International Publication No. WO 00/006550
Patent Literature 13: International Publication No. WO 96/28437
Patent Literature 14: Japanese Unexamined Patent Application, First Publication No. H6-228136
Patent Literature 15: Japanese Unexamined Patent Application, First Publication No. H2-76869
Patent Literature 16: Japanese Unexamined Patent Application, First Publication No. H6-287139
Patent Literature 17: International Publication No. WO 00/07581
Non-Patent Literature 1: J. Amer. Oil Chemists Soc., 51, 200, 1974.
Non-Patent Literature 2: Biochem. Biophys. Acta, 1304, 65, 1996.
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Non-Patent Literature 4: Anderson R. E., Kretzer F. L., Rapp L. M.: “Free Radicals and Eye Diseases”, Adv. Exp. Med. Biol., 366, 73, 1994.
Non-Patent Literature S: Nishigori H., Lee J. W., Yamauchi Y., Iwatsuru M.: “Lipid Peroxide Changes in Glucorticoid-Induced Cataract in Germinated Chicken Embryos and Effects of Ascorbic Acid”, Curr. Eye Res., 5, 37, 1986.
Non-Patent Literature 6: Truscott R. J. W., Augusteyn R. C.: “Action of Mercapto Groups in the Normal and Cataract Human Lens”, Exp. Eye Res., 25, 139, 1977.
Non-Patent Literature 7: Hiramitsu T., Armstrong D.: “Preventive Effects of Antioxidants Against Lipid Peroxidation Reactions in the Retina”, Ophthalmic Research, 23, 196, 1991.
Non-Patent Literature 8: Vitamin Information Center (Tokyo), VIC Newsletter, 105, 4, 2002.
Non-Patent Literature 9: Komura S.: “Cataract and Active Oxygen Free Radicals”, 3, 444, 1992.
Non-Patent Literature 10: Solbach U., Keilhauer C., Knabben H., Wolf S.: “Retina Autofluorescent Images in Age-Related Macular Degeneration”, Retina, 17, 385, 1997.